Immunophenotype of Vestibular Schwannomas

Abstract

Background: Vestibular schwannomas exhibit a uniquely variable natural history of growth, stability, or even spontaneous regression. We hypothesized that a transitory population of immune cells, or immunomodulation of tumors cells, may influence the growth pattern of schwannomas. We therefore sought to characterize the impact of the immune microenvironment on schwannoma behavior. Methods: Forty-eight vestibular schwannomas with preoperative magnetic resonance imaging and 11 with serial imaging were evaluated for presence of immune infiltrates (including the pan-leukocyte marker Cluster of Differentiation (CD)45, CD4 and CD8 T-cell, and CD68 and CD163 macrophages) as well as expression of immunomodulatory regulators (Programmed Death Ligand 1 (PD-L1), Programmed Death Ligand 2 (PD-L2), LAG-3, TIM-3, V-domain Ig Suppressor of T cell Activation). Maximal diameter, volume, and recurrence were annotated. Results: Vestibular schwannomas were characterized by diverse signatures of tumor infiltrating leukocytes and immunomodulatory markers. The median tumor volume was 4.7 cm3 (Interquartile Range (IQR) 1.0–13.0) and maximum diameter was 2.3 cm (IQR 1.5–3.2). Among tumors with serial imaging, the median volumetric growth was 0.04 cm3/mo (IQR 0.01–0.18). Tumor volume and maximum diameter demonstrated strong concordance (R2 = 0.90; p < 0.001). Vestibular schwannoma volume was positively associated with CD4, CD68, and CD163, but not CD8, immune infiltration (all p < 0.05). Tumor growth was positively associated with CD163 and PD-L1 (both p < 0.05). Further, CD163 modified this effect: the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration (R2 = 0.81, p = 0.007). No other immune cell types modified this relationship. These associations were inconsistently observed for maximum diameter and linear growth. Conclusion: Vestibular schwannomas demonstrate variable expression of immune regulatory markers as well as immune infiltrates. Tumor size is associated with immune infiltrates and tumor growth is associated with PD-L1, especially in the presence of M2-subtype macrophages. Volumetric measures may associate with the biological signature more accurately than linear parameters. Future exploration of the role of immune modulation in select schwannomas will further enhance our understanding of the biology of these tumors and suggest potential therapeutic avenues for control of tumor growth.

COX2 expression is associated with preoperative tumor volume but not with volumetric tumor growth in vestibular schwannoma

“…Thus, the recommendation to control tumor growth conservatively with acetyl salicylic acid via COX2 Regarding the preoperative tumor volume, relative higher COX2 expression is associated with larger vestibular schwannoma volume, which was already suggested in our prior study where a correlation of COX2 expression and the tumor extension (Hannover classification) was described [1]. An association of immune cell infiltration and vestibular schwannoma size has also been recently described [2] and could be a possible explanation for this finding. A result that is harder to grasp, is the preoperative tumor volume according to our MIB1 expression results.…”

“…Department of Neurosurgery, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Hoppe-Seyler Street 3, Tübingen, Germany. 2 Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen -Stuttgart, University Hospital Tübingen, Eberhard-Karls-University Tübingen, Tübingen, Germany. 3 Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal.…”

Potential Molecular Biomarkers of Vestibular Schwannoma Growth: Progress and Prospects

“…Consistent with these findings, the levels of macrophage colony-stimulating factor (M-CSF), an important cytokine that stimulates macrophage polarization into an M2-type macrophage, and its synergistic cytokine interleukin-34 (IL-34), are increased in fast-growing VS, suggesting their potential function as promoters of tumor progression (33). Recently, Bi et al demonstrated variable expression of immune regulatory markers as well as immune infiltrates in VS (128). They found both tumor volume and volumetric growth were positively correlated with CD163 expression, and the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration, suggesting a prominent role of immunotherapy in VS treatment (128).…”

“…Recently, Bi et al. demonstrated variable expression of immune regulatory markers as well as immune infiltrates in VS ( 128 ). They found both tumor volume and volumetric growth were positively correlated with CD163 expression, and the relationship between PD-L1 and growth strengthened with increasing CD163 infiltration, suggesting a prominent role of immunotherapy in VS treatment ( 128 ).…”

“…Merlin, whose conformational changes are regulated by RTKs and integrin signals, is also an inhibitor of the pro-inflammatory transcription factor NF-κB ( 30 ). On the other hand, high numbers of tumor infiltrating leukocytes in VS tissues can enhance cell survival, promote tumor growth and degenerative changes through the production of growth factors, cytokines, and MMPs ( 33 , 128 , 158 ). These evidences indicate that the progression of VS appears to be the result of interactions of these dysregulated pathways, drugs that target multiple signaling pathways simultaneously merit further investigation.…”